Our overall goal is to improve the long term biochemical free survival of patients with recurrent prostate carcinoma by altering the current decision algorithm through the ability of advanced molecular imaging to guide the appropriate selection of patients who will benefit from salvage radiotherapy. Approximately 50% of patients who have undergone post-prostatectomy radiotherapy after Prostate Specific Antigen (PSA) failure or biopsy proven prostate bed recurrence manifest subsequent systemic disease, in part, because conventional imaging methods fail to adequately differentiate prostatic from extraprostatic recurrence. In the post-prostatectomy setting, both under-treatment and over- treatment occur based on existing strategies, and appropriately directing radiotherapy is an unmet public health need in this population. We plan to leverage advanced molecular imaging with the positron emission tomography (PET) radiotracer anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (anti-3-[18F]FACBC) which in preliminary data is able to differentiate prostatic from extra-prostatic recurrence even at low PSA levels. Doing so will enable more appropriate selection of patients who will benefit from salvage radiotherapy and to achieve durable response at higher PSA levels than previously believed. We hypothesize that if patients are appropriately selected for salvage radiotherapy with the aid of newly available advanced molecular imaging with anti-3-[18F]FACBC PET-CT, a significantly higher proportion will achieve long-term cure and at higher PSA levels than via conventional treatment algorithms. We also hypothesize that the use of advanced molecular imaging will alter post-prostatectomy radiotherapy algorithms both in decision to treat and in planning volumes. To test these two hypothesis, we plan to conduct a prospective randomized clinical trial in which patients will be treated with salvage radiotherapy after conventional imaging methods in the control arm (A) and with the addition of anti-3-[18F]FACBC PET-CT in the trial arm (B). We will explore the role of anti-3-[18F]FACBC PET-CT in (1) controlling prostate cancer that would otherwise generally not be treated with post- prostatectomy radiotherapy, and improving prostate cancer control in patients that would generally be considered for radiotherapy, (2) guiding radiotherapy decisions, both in the overall decision to offer radiotherapy and in the decision to guide the general radiation field (prostate bed versus pelvis), and (3) influencing the target volume and overlap of normal structures when planning and delivering radiotherapy. The work will have significant implications for improving the outcomes of post-prostatectomy patients, not just for the use of anti-3-[18F]FACBC but for the application of novel imaging to guide post-prostatectomy radiotherapy.